F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
OPINION ARTICLE
Deep brain stimulation in Gilles de la Tourette syndrome: killing several birds with one stone? [version 1; referees: 3 approved] Andreas Hartmann1-3 1Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, CNRS UMR 7225, Paris, France 2Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France 3French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
v1
First published: 07 Sep 2016, 5:2255 (doi: 10.12688/f1000research.9521.1)
Open Peer Review
Latest published: 07 Sep 2016, 5:2255 (doi: 10.12688/f1000research.9521.1)
Abstract In patients with severe, treatment-refractory Gilles de la Tourette syndrome (GTS), deep brain stimulation (DBS) of various targets has been increasingly explored over the past 15 years. The multiplicity of surgical targets is intriguing and may be partly due to the complexity of GTS, specifically the various and frequent associated psychiatric comorbidities in this disorder. Thus, the target choice may not only be aimed at reducing tics but also comorbidities. While this approach is laudable, it also carries the risk to increase confounding factors in DBS trials and patient evaluation. Moreover, I question whether DBS should really be expected to alleviate multiple symptoms at a time. Rather, I argue that tic reduction should remain our primary objective in severe GTS patients and that this intervention may subsequently allow an improved psychotherapeutic and/or pharmacological treatment of comorbidities. Thus, I consider DBS in GTS not as a single solution for all our patients’ ailments but as a stepping stone to improved holistic care made possible by tic reduction.
Referee Status: Invited Referees
1
2
3
report
report
report
version 1 published 07 Sep 2016
1 Andrea Cavanna, University of Birmingham UK 2 Jeremy Stern, St George's Hospital Medical School UK 3 Kevin J. Black, Washington University in St. Louis USA, Shan Siddiqi, Washington University School of Medicine USA
This article is included in the Tics channel. Discuss this article Comments (0)
Corresponding author: Andreas Hartmann ([email protected]) How to cite this article: Hartmann A. Deep brain stimulation in Gilles de la Tourette syndrome: killing several birds with one stone? [version 1; referees: 3 approved] F1000Research 2016, 5:2255 (doi: 10.12688/f1000research.9521.1) Copyright: © 2016 Hartmann A. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. Grant information: The author(s) declared that no grants were involved in supporting this work. Competing interests: No competing interests were disclosed. First published: 07 Sep 2016, 5:2255 (doi: 10.12688/f1000research.9521.1)
F1000Research Page 1 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Deep brain stimulation (DBS) has been used for over 15 years to treat severe forms of Gilles de la Tourette syndrome (GTS) refractory to pharmacological and, more recently, cognitive-behavioral therapies (CBT) (Schrock et al., 2015). Despite the relatively small numbers of patients operated so far, the number of surgical targets is impressive (Porta et al., 2013). The available double-blind trials favor the thalamus and the globus pallidus internus (both anteromedial and posteroventral parts) but the debate if these two are the best targets or if other targets need to be explored remains open (Servello et al., 2016). As we have learnt from Parkinson disease, establishing just one or two consensual DBS targets is a long endeavour which requires time and a large number of patients (Lukins et al., 2014). Providing the latter will certainly be difficult in a comparatively rare disease like GTS. Why so many potential targets in GTS? One of the main reasons appears to be the wish to diminish not only tics but also comorbidities (obsessive-compulsive disorder (OCD), impulsivity, attention deficit hyperactivity disorder (ADHD), anxiety, depression and others) which are present in almost 90% of patients meeting DSM criteria for GTS (Hirschtritt et al., 2015). Specifically, these patients fall into the category named « full-blown GTS » by Robertson (2015) and are also the most likely candidates to undergo surgery. Thus, a tailor-made, individualized approach might indeed make sense instead of including/randomizing patients into studies where a certain diagnostic uniformity is required or at least assumed. I will argue that in an admittedly complex situation, Occam’s razor is the way to go forward. First, there is no GTS without tics. Challenging DSM-5 criteria is understandable but unrealistic (Robertson & Eapen, 2014). In clinical practice, however, even if DSM-5 criteria for GTS are met, we do of course establish the predominant symptoms in terms of impairment. Then, we chose the surgical target which we believe will be best suited to counter the main burden on the patient’s quality of life. This may mean that a patient with severe tics but even more severe OCD might actually be operated predominantly for the latter, targeting the subthalamic nucleus, for instance, which is not a usual target in GTS (Mallet et al., 2008). However, if tics are the main problem, then these should be treated first and foremost, which does not prevent us from evaluating comorbidities pre- and post-op by appropriate scales, as is done anyway in most current trials (Kefalopoulou et al., 2015). But we should be clear, for the time being, that obtaining a direct, surgically-induced effect on
comorbidities will be the cherry on the cake, not something that can be systematically expected, at least based on our current knowledge of basal ganglia circuitry. That, for instance, was the rationale of the Paris group to implant electrodes into the limbic portions of the GPi, hoping to also reduce behavioral manifestations of GTS (Houeto et al., 2005; Welter et al., 2008). In a similar vein, I am doubtful of implanting multiple electrodes in multiple sites in the hope of alleviating surgically a host of neuropsychiatric symptoms; although I admit that in rare, very debilitating cases, this might be an option to consider. My take is rather this: having severe, relentless and debilitating tics tend to cloud comorbidities. In case of successful DBS, other symptoms, rather than being co-treated by electrode implantation, may actually re-emerge. However, the patient is now free to pursue other forms of treatment for these symptoms, for instance psychostimulants for the treatment of ADHD if these previously aggravated tics. Even more importantly, psychotherapeutic approaches thus far impossible, notably cognitive behavioural therapy (CBT), can become feasible. An example from the OCD world concerns patients who underwent a 24 week CBT treatment programme after DBS of the nucleus accumbens (Mantione et al., 2014). Not only did CBT offer further symptom improvement: rather, as the authors note, all patients (n=16) had undergone previous CBT trials (between 1 and 9) which were not only unsuccesful but sometimes counterproductive because they majored anxiety and fear. DBS appeared to alleviate these symptoms and thereby made successful CBT possible. In a similar vein, CBT aimed at further tic reduction could be tried post-op where, pre-op, it was unfeasible. The same applies for psychotherapeutical approaches aiming to improve OCD, depression, anxiety and behavioral problems. Therefore, and in conclusion, I suggest to view DBS in GTS as a window or a stepping stone to a more holistic treatment rather than a single solution for all our patients’ ailments.
Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work.
References
Hirschtritt ME, Lee PC, Pauls DL, et al.: Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome. JAMA Psychiatry. 2015; 72(4): 325–33. PubMed Abstract | Publisher Full Text | Free Full Text
Kefalopoulou Z, Zrinzo L, Jahanshahi M, et al.: Bilateral globus pallidus stimulation for severe Tourette’s syndrome: a double-blind, randomised crossover trial. Lancet Neurol. 2015; 14(6): 595–605. PubMed Abstract | Publisher Full Text
Houeto JL, Karachi C, Mallet L, et al.: Tourette’s syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry. 2005; 76(7): 992–5. PubMed Abstract | Publisher Full Text | Free Full Text
Lukins TR, Tisch S, Jonker B: The latest evidence on target selection in deep brain stimulation for Parkinson’s disease. J Clin Neurosci. 2014; 21(1): 22–7. PubMed Abstract | Publisher Full Text
Page 2 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Mallet L, Polosan M, Jaafari N, et al.: Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med. 2008; 359(20): 2121–34. PubMed Abstract | Publisher Full Text
Mantione M, Nieman DH, Figee M, et al.: Cognitive-behavioural therapy augments the effects of deep brain stimulation in obsessive-compulsive disorder. Psychol Med. 2014; 44(16): 3515–22. PubMed Abstract | Publisher Full Text
Porta M, Cavanna AE, Zekaj E, et al.: Selection of patients with Tourette syndrome for deep brain stimulation surgery. Behav Neurol. 2013; 27(1): 125–31. PubMed Abstract | Publisher Full Text
Robertson MM: A personal 35 year perspective on Gilles de la Tourette syndrome: prevalence, phenomenology, comorbidities, and coexistent psychopathologies. Lancet Psychiatry. 2015; 2(1): 68–87. PubMed Abstract | Publisher Full Text
Robertson MM, Eapen V: Tourette’s: syndrome, disorder or spectrum? Classificatory challenges and an appraisal of the DSM criteria. Asian J Psychiatr. 2014; 11: 106–13. PubMed Abstract | Publisher Full Text
Schrock LE, Mink JW, Woods DW, et al.: Tourette syndrome deep brain stimulation: a review and updated recommendations. Mov Disord. 2015; 30(4): 448–71. PubMed Abstract | Publisher Full Text
Servello D, Zekaj E, Saleh C, et al.: Deep Brain Stimulation in Gilles de la Tourette Syndrome: What Does the Future Hold? A Cohort of 48 Patients. Neurosurgery. 2016; 78(1): 91–100. PubMed Abstract
Welter ML, Mallet L, Houeto JL, et al.: Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Arch Neurol. 2008; 65(7): 952–7. PubMed Abstract | Publisher Full Text
Page 3 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Open Peer Review Current Referee Status: Version 1 Referee Report 28 September 2016
doi:10.5256/f1000research.10256.r16159 Kevin J. Black1, Shan Siddiqi2 1 Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St.
Louis, St. Louis, MO, USA 2 Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA This is an interesting and thoughtful take on the approach to DBS in GTS. Because GTS is a complex neuropsychiatric syndrome with a variety of different symptoms (or comorbidities), it may not be reasonable to assume that all of these symptoms will be alleviated by DBS; to the contrary, they may actually appear to be worsening because they were previously being masked by the tics. As the author suggests, it is impossible to make accurate assessments of a treatment's effect without first appropriately classifying the phenomenology of the illness and/or symptoms being targeted. This article shows familiarity with the literature and clear writing, and is entirely appropriate for an Opinion Article. We add a few comments, hopefully to further the discussion. The author argues well for focusing clinical trials for DBS in GTS on one problem at a time, namely tics. However, as he notes, the great majority of patients with GTS have clinical features other than tics. Gilbert and Buncher (2005)1 include this observation of multiple symptoms as one of several features that complicate performing and interpreting clinical trials in GTS. Focusing DBS on the most problematic symptom in each patient may even prove to produce better results than focusing DBS on tics. But we have insufficient data to make such a judgment. The issues identified by Prof. Hartmann highlight the critical importance of further clinical trials and of registering all DBS experience in GTS2. One trivial note: Substitute “exacerbated” for the word “majored” near the end of the article. Shan H. Siddiqi Kevin J. Black References 1. Gilbert DL, Buncher CR: Assessment of scientific and ethical issues in two randomized clinical trial designs for patients with Tourette's syndrome: a model for studies of multiple neuropsychiatric diagnoses. J Neuropsychiatry Clin Neurosci. 2005; 17 (3): 324-32 PubMed Abstract | Publisher Full Text 2. Deeb W, Rossi PJ, Porta M, Visser-Vandewalle V, Servello D, Silburn P, Coyne T, Leckman JF, Foltynie T, Hariz M, Joyce EM, Zrinzo L, Kefalopoulou Z, Welter ML, Karachi C, Mallet L, Houeto JL, Shahed-Jimenez J, Meng FG, Klassen BT, Mogilner AY, Pourfar MH, Kuhn J, Ackermans L, Kaido T, F1000Research Page 4 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Shahed-Jimenez J, Meng FG, Klassen BT, Mogilner AY, Pourfar MH, Kuhn J, Ackermans L, Kaido T, Temel Y, Gross RE, Walker HC, Lozano AM, Khandhar SM, Walter BL, Walter E, Mari Z, Changizi BK, Moro E, Baldermann JC, Huys D, Zauber SE, Schrock LE, Zhang JG, Hu W, Foote KD, Rizer K, Mink JW, Woods DW, Gunduz A, Okun MS: The International Deep Brain Stimulation Registry and Database for Gilles de la Tourette Syndrome: How Does It Work?. Front Neurosci. 2016; 10: 170 PubMed Abstract | Publisher Full Text We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Competing Interests: No competing interests were disclosed. Referee Report 23 September 2016
doi:10.5256/f1000research.10256.r16161 Jeremy Stern Department of Neurology, St George’s Hospital, St George's Hospital Medical School, London, UK Professor Hartmann's opinion article is a clear-thinking and original critique of the directions that DBS for GTS is taking. The field is perhaps expanding faster than uncertainties are being addressed, partly due to the heterogenous nature of the condition and the possibility of several different surgical targets- variables that he surveys from an interesting perspective. I agree with him and Professor Cavanna that the practice of selecting modified surgical targets for tics based on comorbidites may lack a good evidence base, but the fundamental problem is establishing how to best to treat tics with DBS, including the prediction of beneficial effect for individual patients.The notion of DBS in GTS as an enabling therapy to allow conventional management strategies to be more successful needs further exploration and may prove an important principle.
I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Competing Interests: No competing interests were disclosed. Referee Report 19 September 2016
doi:10.5256/f1000research.10256.r16164 Andrea Cavanna Department of Neuropsychiatry, University of Birmingham, Birmingham, UK I found Andreas Hartmann’s considerations on the use of Deep Brain Stimulation (DBS) for patients with Tourette syndrome (TS) both clinically sensible and thought-provoking. The article is clearly written and the take-home message is convincingly argued: patients with TS who are candidates to DBS present by definition with a clinical picture characterised by highly severe and refractory tics. Rather than considering DBS as a panacea for the multifaceted neurobehavioural spectrum complicating patients’ presentations, the focus (and expectations) of DBS should remain anchored to tic alleviation. From a practical point of view, it has been observed that the DBS procedure can have wide-ranging effects, however the approach F1000Research Page 5 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
view, it has been observed that the DBS procedure can have wide-ranging effects, however the approach of a priori targeting multiple symptoms at the same time (“killing several birds with one stone”) can be prone to theoretical and clinical fallacies. Conversely, it would be interesting to test the sequential approach proposed by the author by systematically assessing changes in health-related quality of life in patients undergoing tic-focused neuromodulation, followed by specific therapeutic interventions for the residual behavioural co-morbidities. I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Competing Interests: No competing interests were disclosed.
F1000Research Page 6 of 6
OPINION ARTICLE
Deep brain stimulation in Gilles de la Tourette syndrome: killing several birds with one stone? [version 1; referees: 3 approved] Andreas Hartmann1-3 1Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, CNRS UMR 7225, Paris, France 2Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France 3French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
v1
First published: 07 Sep 2016, 5:2255 (doi: 10.12688/f1000research.9521.1)
Open Peer Review
Latest published: 07 Sep 2016, 5:2255 (doi: 10.12688/f1000research.9521.1)
Abstract In patients with severe, treatment-refractory Gilles de la Tourette syndrome (GTS), deep brain stimulation (DBS) of various targets has been increasingly explored over the past 15 years. The multiplicity of surgical targets is intriguing and may be partly due to the complexity of GTS, specifically the various and frequent associated psychiatric comorbidities in this disorder. Thus, the target choice may not only be aimed at reducing tics but also comorbidities. While this approach is laudable, it also carries the risk to increase confounding factors in DBS trials and patient evaluation. Moreover, I question whether DBS should really be expected to alleviate multiple symptoms at a time. Rather, I argue that tic reduction should remain our primary objective in severe GTS patients and that this intervention may subsequently allow an improved psychotherapeutic and/or pharmacological treatment of comorbidities. Thus, I consider DBS in GTS not as a single solution for all our patients’ ailments but as a stepping stone to improved holistic care made possible by tic reduction.
Referee Status: Invited Referees
1
2
3
report
report
report
version 1 published 07 Sep 2016
1 Andrea Cavanna, University of Birmingham UK 2 Jeremy Stern, St George's Hospital Medical School UK 3 Kevin J. Black, Washington University in St. Louis USA, Shan Siddiqi, Washington University School of Medicine USA
This article is included in the Tics channel. Discuss this article Comments (0)
Corresponding author: Andreas Hartmann ([email protected]) How to cite this article: Hartmann A. Deep brain stimulation in Gilles de la Tourette syndrome: killing several birds with one stone? [version 1; referees: 3 approved] F1000Research 2016, 5:2255 (doi: 10.12688/f1000research.9521.1) Copyright: © 2016 Hartmann A. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. Grant information: The author(s) declared that no grants were involved in supporting this work. Competing interests: No competing interests were disclosed. First published: 07 Sep 2016, 5:2255 (doi: 10.12688/f1000research.9521.1)
F1000Research Page 1 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Deep brain stimulation (DBS) has been used for over 15 years to treat severe forms of Gilles de la Tourette syndrome (GTS) refractory to pharmacological and, more recently, cognitive-behavioral therapies (CBT) (Schrock et al., 2015). Despite the relatively small numbers of patients operated so far, the number of surgical targets is impressive (Porta et al., 2013). The available double-blind trials favor the thalamus and the globus pallidus internus (both anteromedial and posteroventral parts) but the debate if these two are the best targets or if other targets need to be explored remains open (Servello et al., 2016). As we have learnt from Parkinson disease, establishing just one or two consensual DBS targets is a long endeavour which requires time and a large number of patients (Lukins et al., 2014). Providing the latter will certainly be difficult in a comparatively rare disease like GTS. Why so many potential targets in GTS? One of the main reasons appears to be the wish to diminish not only tics but also comorbidities (obsessive-compulsive disorder (OCD), impulsivity, attention deficit hyperactivity disorder (ADHD), anxiety, depression and others) which are present in almost 90% of patients meeting DSM criteria for GTS (Hirschtritt et al., 2015). Specifically, these patients fall into the category named « full-blown GTS » by Robertson (2015) and are also the most likely candidates to undergo surgery. Thus, a tailor-made, individualized approach might indeed make sense instead of including/randomizing patients into studies where a certain diagnostic uniformity is required or at least assumed. I will argue that in an admittedly complex situation, Occam’s razor is the way to go forward. First, there is no GTS without tics. Challenging DSM-5 criteria is understandable but unrealistic (Robertson & Eapen, 2014). In clinical practice, however, even if DSM-5 criteria for GTS are met, we do of course establish the predominant symptoms in terms of impairment. Then, we chose the surgical target which we believe will be best suited to counter the main burden on the patient’s quality of life. This may mean that a patient with severe tics but even more severe OCD might actually be operated predominantly for the latter, targeting the subthalamic nucleus, for instance, which is not a usual target in GTS (Mallet et al., 2008). However, if tics are the main problem, then these should be treated first and foremost, which does not prevent us from evaluating comorbidities pre- and post-op by appropriate scales, as is done anyway in most current trials (Kefalopoulou et al., 2015). But we should be clear, for the time being, that obtaining a direct, surgically-induced effect on
comorbidities will be the cherry on the cake, not something that can be systematically expected, at least based on our current knowledge of basal ganglia circuitry. That, for instance, was the rationale of the Paris group to implant electrodes into the limbic portions of the GPi, hoping to also reduce behavioral manifestations of GTS (Houeto et al., 2005; Welter et al., 2008). In a similar vein, I am doubtful of implanting multiple electrodes in multiple sites in the hope of alleviating surgically a host of neuropsychiatric symptoms; although I admit that in rare, very debilitating cases, this might be an option to consider. My take is rather this: having severe, relentless and debilitating tics tend to cloud comorbidities. In case of successful DBS, other symptoms, rather than being co-treated by electrode implantation, may actually re-emerge. However, the patient is now free to pursue other forms of treatment for these symptoms, for instance psychostimulants for the treatment of ADHD if these previously aggravated tics. Even more importantly, psychotherapeutic approaches thus far impossible, notably cognitive behavioural therapy (CBT), can become feasible. An example from the OCD world concerns patients who underwent a 24 week CBT treatment programme after DBS of the nucleus accumbens (Mantione et al., 2014). Not only did CBT offer further symptom improvement: rather, as the authors note, all patients (n=16) had undergone previous CBT trials (between 1 and 9) which were not only unsuccesful but sometimes counterproductive because they majored anxiety and fear. DBS appeared to alleviate these symptoms and thereby made successful CBT possible. In a similar vein, CBT aimed at further tic reduction could be tried post-op where, pre-op, it was unfeasible. The same applies for psychotherapeutical approaches aiming to improve OCD, depression, anxiety and behavioral problems. Therefore, and in conclusion, I suggest to view DBS in GTS as a window or a stepping stone to a more holistic treatment rather than a single solution for all our patients’ ailments.
Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work.
References
Hirschtritt ME, Lee PC, Pauls DL, et al.: Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome. JAMA Psychiatry. 2015; 72(4): 325–33. PubMed Abstract | Publisher Full Text | Free Full Text
Kefalopoulou Z, Zrinzo L, Jahanshahi M, et al.: Bilateral globus pallidus stimulation for severe Tourette’s syndrome: a double-blind, randomised crossover trial. Lancet Neurol. 2015; 14(6): 595–605. PubMed Abstract | Publisher Full Text
Houeto JL, Karachi C, Mallet L, et al.: Tourette’s syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry. 2005; 76(7): 992–5. PubMed Abstract | Publisher Full Text | Free Full Text
Lukins TR, Tisch S, Jonker B: The latest evidence on target selection in deep brain stimulation for Parkinson’s disease. J Clin Neurosci. 2014; 21(1): 22–7. PubMed Abstract | Publisher Full Text
Page 2 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Mallet L, Polosan M, Jaafari N, et al.: Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med. 2008; 359(20): 2121–34. PubMed Abstract | Publisher Full Text
Mantione M, Nieman DH, Figee M, et al.: Cognitive-behavioural therapy augments the effects of deep brain stimulation in obsessive-compulsive disorder. Psychol Med. 2014; 44(16): 3515–22. PubMed Abstract | Publisher Full Text
Porta M, Cavanna AE, Zekaj E, et al.: Selection of patients with Tourette syndrome for deep brain stimulation surgery. Behav Neurol. 2013; 27(1): 125–31. PubMed Abstract | Publisher Full Text
Robertson MM: A personal 35 year perspective on Gilles de la Tourette syndrome: prevalence, phenomenology, comorbidities, and coexistent psychopathologies. Lancet Psychiatry. 2015; 2(1): 68–87. PubMed Abstract | Publisher Full Text
Robertson MM, Eapen V: Tourette’s: syndrome, disorder or spectrum? Classificatory challenges and an appraisal of the DSM criteria. Asian J Psychiatr. 2014; 11: 106–13. PubMed Abstract | Publisher Full Text
Schrock LE, Mink JW, Woods DW, et al.: Tourette syndrome deep brain stimulation: a review and updated recommendations. Mov Disord. 2015; 30(4): 448–71. PubMed Abstract | Publisher Full Text
Servello D, Zekaj E, Saleh C, et al.: Deep Brain Stimulation in Gilles de la Tourette Syndrome: What Does the Future Hold? A Cohort of 48 Patients. Neurosurgery. 2016; 78(1): 91–100. PubMed Abstract
Welter ML, Mallet L, Houeto JL, et al.: Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Arch Neurol. 2008; 65(7): 952–7. PubMed Abstract | Publisher Full Text
Page 3 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Open Peer Review Current Referee Status: Version 1 Referee Report 28 September 2016
doi:10.5256/f1000research.10256.r16159 Kevin J. Black1, Shan Siddiqi2 1 Departments of Psychiatry, Neurology, Radiology, and Neuroscience, Washington University in St.
Louis, St. Louis, MO, USA 2 Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA This is an interesting and thoughtful take on the approach to DBS in GTS. Because GTS is a complex neuropsychiatric syndrome with a variety of different symptoms (or comorbidities), it may not be reasonable to assume that all of these symptoms will be alleviated by DBS; to the contrary, they may actually appear to be worsening because they were previously being masked by the tics. As the author suggests, it is impossible to make accurate assessments of a treatment's effect without first appropriately classifying the phenomenology of the illness and/or symptoms being targeted. This article shows familiarity with the literature and clear writing, and is entirely appropriate for an Opinion Article. We add a few comments, hopefully to further the discussion. The author argues well for focusing clinical trials for DBS in GTS on one problem at a time, namely tics. However, as he notes, the great majority of patients with GTS have clinical features other than tics. Gilbert and Buncher (2005)1 include this observation of multiple symptoms as one of several features that complicate performing and interpreting clinical trials in GTS. Focusing DBS on the most problematic symptom in each patient may even prove to produce better results than focusing DBS on tics. But we have insufficient data to make such a judgment. The issues identified by Prof. Hartmann highlight the critical importance of further clinical trials and of registering all DBS experience in GTS2. One trivial note: Substitute “exacerbated” for the word “majored” near the end of the article. Shan H. Siddiqi Kevin J. Black References 1. Gilbert DL, Buncher CR: Assessment of scientific and ethical issues in two randomized clinical trial designs for patients with Tourette's syndrome: a model for studies of multiple neuropsychiatric diagnoses. J Neuropsychiatry Clin Neurosci. 2005; 17 (3): 324-32 PubMed Abstract | Publisher Full Text 2. Deeb W, Rossi PJ, Porta M, Visser-Vandewalle V, Servello D, Silburn P, Coyne T, Leckman JF, Foltynie T, Hariz M, Joyce EM, Zrinzo L, Kefalopoulou Z, Welter ML, Karachi C, Mallet L, Houeto JL, Shahed-Jimenez J, Meng FG, Klassen BT, Mogilner AY, Pourfar MH, Kuhn J, Ackermans L, Kaido T, F1000Research Page 4 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
Shahed-Jimenez J, Meng FG, Klassen BT, Mogilner AY, Pourfar MH, Kuhn J, Ackermans L, Kaido T, Temel Y, Gross RE, Walker HC, Lozano AM, Khandhar SM, Walter BL, Walter E, Mari Z, Changizi BK, Moro E, Baldermann JC, Huys D, Zauber SE, Schrock LE, Zhang JG, Hu W, Foote KD, Rizer K, Mink JW, Woods DW, Gunduz A, Okun MS: The International Deep Brain Stimulation Registry and Database for Gilles de la Tourette Syndrome: How Does It Work?. Front Neurosci. 2016; 10: 170 PubMed Abstract | Publisher Full Text We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Competing Interests: No competing interests were disclosed. Referee Report 23 September 2016
doi:10.5256/f1000research.10256.r16161 Jeremy Stern Department of Neurology, St George’s Hospital, St George's Hospital Medical School, London, UK Professor Hartmann's opinion article is a clear-thinking and original critique of the directions that DBS for GTS is taking. The field is perhaps expanding faster than uncertainties are being addressed, partly due to the heterogenous nature of the condition and the possibility of several different surgical targets- variables that he surveys from an interesting perspective. I agree with him and Professor Cavanna that the practice of selecting modified surgical targets for tics based on comorbidites may lack a good evidence base, but the fundamental problem is establishing how to best to treat tics with DBS, including the prediction of beneficial effect for individual patients.The notion of DBS in GTS as an enabling therapy to allow conventional management strategies to be more successful needs further exploration and may prove an important principle.
I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Competing Interests: No competing interests were disclosed. Referee Report 19 September 2016
doi:10.5256/f1000research.10256.r16164 Andrea Cavanna Department of Neuropsychiatry, University of Birmingham, Birmingham, UK I found Andreas Hartmann’s considerations on the use of Deep Brain Stimulation (DBS) for patients with Tourette syndrome (TS) both clinically sensible and thought-provoking. The article is clearly written and the take-home message is convincingly argued: patients with TS who are candidates to DBS present by definition with a clinical picture characterised by highly severe and refractory tics. Rather than considering DBS as a panacea for the multifaceted neurobehavioural spectrum complicating patients’ presentations, the focus (and expectations) of DBS should remain anchored to tic alleviation. From a practical point of view, it has been observed that the DBS procedure can have wide-ranging effects, however the approach F1000Research Page 5 of 6
F1000Research 2016, 5:2255 Last updated: 28 SEP 2016
view, it has been observed that the DBS procedure can have wide-ranging effects, however the approach of a priori targeting multiple symptoms at the same time (“killing several birds with one stone”) can be prone to theoretical and clinical fallacies. Conversely, it would be interesting to test the sequential approach proposed by the author by systematically assessing changes in health-related quality of life in patients undergoing tic-focused neuromodulation, followed by specific therapeutic interventions for the residual behavioural co-morbidities. I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Competing Interests: No competing interests were disclosed.
F1000Research Page 6 of 6
